# Mechanisms of cardiac and pulmonary fibrosis in relation to TGF-beta signaling and miR-145 function

> **NIH NIH R01** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2020 · $411,019

## Abstract

SUMMARY
We identified a novel function for microRNA miR145 in the suppression of cardiac fibrosis using miR145-
deficient mice. It has also been reported that miR145 enhances pulmonary fibrosis, and that miR145 can drive
myofibroblast (myoF) differentiation within both cardiac and lung fibroblasts (Fbs). Together these data suggest
that mechanistic differences between cardiac and pulmonary fibrosis may reflect differences in cell type
contribution and dissimilar actions of miR145 upon Fbs. Preliminary data reveal that miR145 targets
components of the profibrotic TGFß signaling pathway, which is a central mediator of cardiac and pulmonary
fibrosis. Furthermore, we have shown that a downstream TGFß effector, Periostin (Postn) is upregulated in
myoFs in cardiac and pulmonary fibrosis. Postn has been proven to play an important role in fibrogenesis in
many organs in which it is activated during the Fb-myoF transition. Additional preliminary data reveal that
within the heart, systemic deletion of Postn correlates with decreased fibrosis but unlike the heart, the absence
of Postn results in elevated lung fibrosis. The overall objective of this application is to define the distinct cell-
specific mechanisms that contribute to cardiac and pulmonary fibrosis. Our data suggest that suppression of
TGFß signaling by miR145 and/or removal of TGFß-responsive downstream effectors like Postn may be
employed to modulate fibrosis. Our central hypothesis is that cardiac and pulmonary fibrosis exhibit different
mechanisms due to variances in the contributing cell populations and organ-specific transcriptional milieu.
While TGFß signaling drives both pathologies and upregulation of Postn, the cell microenvironment dictates
disease progression. Cardiac fibrosis manifests primarily through stress-induced activation of CFs, while
pulmonary fibrosis involves epithelial-to-mesenchymal transitions, inflammation and resident Fb activation.
Using cell-specific loss-of-function and gain-of-function strategies to modulate miR145, we will determine the
cell types that contribute to the contrasting functions of miR145 in cardiac and pulmonary fibrosis. This co-
investigator team is well positioned to test this hypothesis, with a prior track record of collaboration and
expertise. The Lilly lab has generated a novel miR145 transgenic mouse strain, and is experienced with
microRNA analyses. The Conway lab brings extensive experience in both cardiac and pulmonary disease
models, and expertise in Postn and Fb activation. The goal of the aims is to determine the cell type-specific
requirement of miR145 to regulate fibrosis with the intent of elucidating novel distinctive mechanisms
associated with pulmonary and cardiac fibrosis. Aim 1) Delineate the mechanisms that differentially govern
cardiac and pulmonary fibrosis. Aim 2) Determine if lineage-restricted overexpression of a miR145 transgene
alters pulmonary and/or cardiac fibrosis. These expected outcomes will elucidate mechanisms c...

## Key facts

- **NIH application ID:** 10017293
- **Project number:** 5R01HL135657-04
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** Simon James Conway
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $411,019
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017293

## Citation

> US National Institutes of Health, RePORTER application 10017293, Mechanisms of cardiac and pulmonary fibrosis in relation to TGF-beta signaling and miR-145 function (5R01HL135657-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10017293. Licensed CC0.

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